This proposal is focused on studies to elucidate the mechanisms of radiation-induced cognitive dysfunction. This is an important problem because 30-50% of the patients who survive more than 18 months after whole-brain irradiation (WBI) suffer from severe cognitive deficits. We have characterized a rat model of radiation-induced cognitive dysfunction using a fractionated dose of WBI that is biologically equivalent doses typically given to brain tumor patients. During those studies, we made the novel finding that the density of the capillary bed decreased in three areas of the brain, including the hippocampus which is involved in learning and memory. This decrease occurred as early as 10 weeks post-irradiation. There was partial recovery of the capillary bed by 20 weeks, and thereafter a decline in capillary density in the irradiated rats paralleled that observed in the controls, out to one year post-irradiation. The capillary loss occurred much earlier than vascular damage previously reported for high single doses of WBI and much earlier than the appearance of cognitive deficits, which occurred 6-9 months post-irradiation, as measured in a radial-arm maze. These findings suggest that a cascade of events, beginning with capillary loss, leads eventually to cognitive dysfunction. However, the limited numbers of animals (2-6) per group and sampling times, the lack of a quantitative assessment of demyelination and glial cell damage, and the absence of dose-response data leave it uncertain whether there is a causal relationship between the capillary loss and the cognitive deficits. The specific aims of the present grant proposal should strengthen the evidence. If early damage to the blood vessels can be correlated with the late onset of cognitive deficits, it will not only have important mechanistic implications, but it would also provide an early biomarker for testing therapeutic interventions designed to ameliorate radiation-induced brain dysfunction. Such therapeutic intervention studies could potentially be performed in as little as 10 weeks.